1. Field of the Invention
The present invention relates to a radiation-resistant microporous membrane having a hydrophobicity gradient, to a method for the preparation thereof, to the use of the membrane in the sterilizing filtration of gaseous fluids and to the use of the membrane as a liquid barrier in liquid-containing systems to be vented.
2. Description of the Related Art
In the fields of foodstuff and pharmaceutical manufacturing and of biotechnological production and in healthcare, sterile operations are a prerequisite for commercial success. For pathogen-free operations, it is important not only that solutions to be processed are sterile, but also that work equipment and manufacturing equipment are pathogen-free. The latter group includes preparation, mixing, transport or storage tanks made of metal, glass or plastic, and also reactors and fermenters, more particularly those having flexible plastic walls for single use.
Customary process steps in the industrial operation of reusable metal containers are cleaning and sterilization using superheated steam, filling, temperature adjustment, transport and emptying of liquids. With the exception of the cleaning step, the processes mentioned require a sterile-filtering venting element (venting device) at at least one tank opening (a flange) in order to prevent damage to the manufacturing equipment due to elevated or reduced pressure and, at the same time, to ensure that the solution-contacted interior is pathogen-free during venting.
The venting element is the interface between a preferably sterile, liquid-containing tank interior (e.g. as a liquid barrier in dialysis devices, infusion solution tanks or in fermenters) and an external, preferably nonsterile atmosphere. The actual partition medium selected in the venting element is, in most cases, a sterile-filtering membrane filter composed of a synthetic polymer. In rare cases, a nonwoven composed of synthetic fibrous material is incorporated.
In most cases, synthetic polymers have hydrophobic surface properties which can be attributed to the intrinsic hydrophobicity of the synthetic materials. The hydrophobicity is a material constant. It is caused by the extramolecular interactions of the atom groups forming the polymer.
Surfaces having a contact angle of more than 90° with respect to water are referred to as hydrophobic. Hydrophobic substances are not miscible or wettable with water. The substances are usually nonpolar. Their surface tension at 20° C. is below 72 mN/m.
The hydrophobic character of the sterile-filtering partition medium is a prerequisite for incorporation into a venting element for two different reasons. Firstly, a closed water film must not form on the surface of or within the partition medium upon contact with water or medium or, more particularly, water vapor (when steaming or gassing bioreactors). The water film would prevent pressure equalization (gas exchange) between the internal and external atmosphere and, as a result, compromise the mechanical integrity of the tank. In this case, it is advantageous when the partition medium exhibits strong hydrophobicity (e.g. as in the case of fluorine-containing organic polymers) through to an oleophobic character.
In the case of venting applications, use is made of customary materials for membrane filters, such as polytetrafluoroethylene (PTFE), polypropylene (PP) and polyvinylidene fluoride (PVDF), and in the case of fibrous material, use is made of polyethylene (PE).
Secondly, a hydrophobic partition medium allows wetting with simple organic solvents (e.g. alcohol) in order to check the integrity of the partition medium before and after use. The partition medium is checked by means of the pressure-hold test and/or the bubble-point test. For the pressure-hold test, pressure is applied to the wetted membrane. For this purpose, up to about 80% of the bubble-point value to be expected is selected for example. This pressure is subsequently observed for a few minutes. During this time, the pressure drop must not exceed a particular limit. Thereafter, the bubble point can be determined under continued elevation of the pressure. At the precise moment at which a continuous discharge of air bubbles can be seen on the nonpressurized side of the membrane, the pressure reached is read on the manometer. Taking account of the membrane properties, it is subsequently possible to calculate the largest pore and to estimate the retention property of the membrane.
In the abovementioned case, a filter medium which is oleophobic throughout is disadvantageous because simple homogeneous wetting is not possible with many organic solvents which are customary for the integrity tests.
The integrity (=faultless sealing of the filter medium in the filtration housing, largest pore for estimating retention properties) of filtration products having an oleophobic filter medium can be ascertained by determining the intrusion pressure. Here, the property of pressurized liquids whose surface tension is greater than that of the nonwetting porous system to enter the pores and penetrate them convectively upon attainment of a minimum pressure (=intrusion pressure) is utilized. The higher the intrusion pressure, the smaller the radius of the first penetrated largest pore. For this purpose, the filter-medium surface which is nonwetting under standard conditions (room temperature, atmospheric pressure) is completely overlaid with the test liquid. Similarly to the bubble-point method for ascertaining the bubble pass-through point on wetting systems, the liquid is applied with increasing pressure. Once test liquid appears on the nonpressurized side of the filter medium, the intrusion pressure has been reached, the level of which is a measure of the radius (diameter) of the largest pore in the oleophobic filter medium.
Using the same experimental setup, it is possible to carry out a pressure-hold test, in which the test liquid is applied at a pressure of about 80% of the intrusion pressure to be expected.
Oleophobic substances, which are distinguished by an especially high hydrophobicity, are not miscible or wettable with oils and other nonpolar substances. Their surface tension at 20° C. is less than 21 mN/m.
Water or purely aqueous solutions of salts (e.g. 0.9% NaCl, buffer) are processed in only a few applications. In many cases, there are water-based formulations containing not only inorganic salts but also wetting agents, organic solvents, proteins, vitamins and nutrients, which as a whole lower the surface tension of the solvent used and thus alter its wetting behavior with respect to solids. In these cases, it is recommended to contact the porous partition medium with the liquid for testing purposes in order to check the wetting behavior.
In the prior art, various methods for providing membranes having both hydrophobic and oleophobic properties have been described.
US 2008/0237117 A1 describes asymmetric membranes which have a multilayer structure and which consist of a hydrophobic base membrane. The hydrophobic base membrane can be formed from any desired hydrophobic polymers, for example from expanded PTFE.
The hydrophobic membrane has on one of its main surfaces a discontinuous coating which does not seal the pores and which is composed of an oleophobic polymer (e.g. a fluorinated polymer).
The membrane oleophobicized in such a one-sided manner can either have on its second opposing hydrophobic main surface a continuous, pore-covering, hydrophilic coating, or it is laminated via an adhesive onto a second hydrophobic membrane also having an oleophobic coating such that the two oleophobic coatings of the membrane composite point outward. US 2008/0237117 A1 describes neither membranes having gradually gradated hydrophobic properties across the membrane cross-section nor methods for preparing membranes having a hydrophobicity gradient.
WO 2009/065092 A1 discloses microporous textile-reinforced polyolefin membranes composed of PE, the main surfaces of which are selectively hydrophobicized or oleophobicized by means of an impregnation method.
The aforementioned impregnation method makes it possible to render a main surface of the microporous PE membrane oleophobic with a fluorine substituent-containing polymer, while the opposing main surface of the PE membrane retains its hydrophobic starting properties.
The disadvantages of these membranes known from WO 2009/065092 A1, which have proved themselves as a matter of principle as breathable materials in clothing manufacturing, are that they do not exhibit sufficient resistance to high-energy radiation, for example gamma radiation, and that they exhibit only insufficient temperature stability.
U.S. Pat. No. 5,554,414 discloses microporous composite membranes whose entire inner and outer surface is coated with a crosslinked polymer which is formed from a fluorine substituent-containing monomer and a crosslinker.
Coating the microporous membrane results in it not being wettable by a liquid having a surface tension of greater than 21 mN/m. U.S. Pat. No. 5,554,414 describes neither membranes having gradually gradated hydrophobic properties across the membrane cross-section (i.e. having a hydrophobicity gradient) nor methods for preparation thereof.
U.S. Pat. No. 6,579,342 B2 discloses venting filters whose hydrophobic base material (e.g. polysulfone or PVDF) is coated with an oleophobic oligomer which is functionalized with perfluoroalkyl groups and sulfone groups. The coating is applied to the surface of the base material by grafting the aforementioned oligomer. This document, too, does not disclose membranes having a hydrophobicity gradient.
In recent years, the trend toward single-use usage of plastic tanks in the processing of liquids has intensified. In contrast to metal tanks, tanks composed of organic polymers are not autoclaved for the purpose of sterilization, but are usually made pathogen-free for use by means of high-energy radiation, for example gamma radiation. Irradiation is a physical process which takes place at room temperature. The sterilizing (killing) action of the high-energy radiation is based on bond cleavage within the organic matter penetrated by gamma radiation.
Organic polymers are damaged to differing extents by high-energy radiation. Polytetrafluoroethylene (PTFE), polypropylene (PP) and polyvinyl chloride (PVC) in particular experience a dramatic weakening of their mechanical stability, whereas aromatic polymers such as polyether sulfones (polysulfone (PSU), polyethersulfone (PES)) and polyimides (PI) show only minor changes. Medium tolerance to gamma radiation is exhibited by, for example, polyethylene (PE), polyester (PET) and polyvinylidene fluoride (PVDF) (cf. table 1).
TABLE 1OrganicMax. short-termResistance rangepolymerusage temperature (° C.)**(kGy)*PTFE300   5POM150   15PP140   20PVC100   50PA 6.6200   50PMMA100  100PE120  500PVDF150  1000PS90  1000PC160  1000PET200  1000PBT165  1000PEEK30010 000PI40010 000PAI30010 000PSU17010 000PES26010 000POM: polyoxymethylene;PA 6.6: nylon 6,6, polyhexamethylene adipamide;PMMA: polymethyl methacrylate;PC: polycarbonate;PAI: polyamide-imide;PEEK: polyetheretherketone;PS: polystyrene;PBT: polybutylene terephthalate*Resistance range in the case of gamma irradiation: data sheet from BGS (supplier: Beta-Gamma-Service GmbH & Co. KG, Fritz-Kotz-Strasse 16, 51674 Wiehl, Germany)**Temperature values from “Saechtling Kunststoff Taschenbuch” (“Saechtling Plastics Handbook”), ed. K. Oberbach, C. Hanser Verlag, 27th edition, table 5.14
A summary of the material properties of currently commonly used porous partition media from table 1 reveals that none of the materials can satisfy the sum of the requirements and none can thus be used as a universal filter medium for sterile venting applications: hydrophobic PTFE exhibits, together with excellent temperature stability, minimal resistance to sterilizing radiation treatment. Hydrophobic PE is disadvantaged owing to low temperature stability and hydrophobic PP is disadvantaged owing to insufficient radiation resistance (cf. table 1).
In the case of polymers having a purely aliphatic main chain (e.g. PE, PTFE) or in the case of those having at least two consecutive saturated carbon atoms between aromatic chain segments (e.g. PET, PC), high-energy radiation leads to greater impairment of the mechanical strength thereof than in the case of aromatic main-chain polymers which are built up exclusively from aromatic building blocks, from an aromatic chain (e.g. PSU, PES) interrupted by only one nonaromatic main-chain atom or from aromatic building blocks which are linked to one another by means of a nonaromatic ring system.
The majority of the resistance ranges for gamma radiation, as described in the literature for polymeric materials, is based on mechanical measurements on solid shaped articles (e.g. data sheet from BGS (Beta-Gamma-Service, 51674 Wiehl, Germany)). Filter media are porous films or fibrous materials, the inner porosity of which is between 50% and 80%. The low material density of the pore-forming matrix increases the loss of strength of porous partition media owing to the damaging action of high-energy radiation.
It is an object of the present invention to provide a microporous membrane, the first external oleophobic main surface of which is not wettable with hydrophilic substances, such as lower alcohols (e.g. ethanol, isopropanol) or detergent-containing aqueous solutions, whereas the second external hydrophobic main surface of the membrane is wettable with the aforementioned hydrophilic substances and is amenable to an integrity test or being checked, wherein the membrane according to the invention allows, at the same time, temperature and radiation treatment.